The present invention is compounds, methods, compositions, and devices for preventing infection by sexually transmitted HIV.
The retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. Since it emerged as a public health threat in the early 1980""s, efforts to control or eradicate the disease have focused principally on options for treating the disease after an individual has already become infected.
The use of condoms provides a substantial degree of protection against transmission of HIV infections during sexual intercourse. However, the use of condoms is not 100% effective against the transmission of HIV. Moreover, couples often do not use condoms. A topical composition that could be inserted into the vagina or rectum by a foam, gel, sponge or other form, or which could be topically applied to the male genitalia, would in many cases be preferred over condoms. Moreover, the prophylactic effectiveness of condoms could be improved by including a suitable microbicide in the lubricant coated on the exterior of the condom. However, to date little progress has been made to develop an effective topical composition against the transmission of HIV.
Most work to develop topical HIV prophylactic compositions has focused on the use of surfactants and buffers, such as the over-the-counter product nonoxynol-9. Surfactants and detergents disrupt microbial and sperm membranes by lysis and emulsification. Surfactant-containing creams and gels have the advantage of being very broad in their killing ability, and thus can kill the HIV virus and viruses associated with other sexually transmitted diseases. The use of surfactants and buffers is, however, substantially limited by the damage they can cause to cell membranes. In the vagina, nonoxynol-9 has been shown to thin vaginal walls. In the rectum, nonoxynol-9 can cause rectum walls to slough off.
Other virusidal compositions being investigated for use as HIV virusides include carageenan and other large sulfated polysaccharides that stick to viral envelopes and possibly shield cell membranes. Philips D M, xe2x80x9cOf Mice and Menxe2x80x94Assaying Vaginal Virusides,xe2x80x9d Virusides 2000, Mar. 13-16, 2000, Alexandria Va., page 12, abstract A20. Monoclonal antibodies have also been proposed as HIV prophylactics, and some antibodies have shown a promising degree of protection. (Mascola J et al., xe2x80x9cRole of IgG Antibody in Protection against Vaginal Transmission of an HIV-1/SIV Chimeric Virus,xe2x80x9d Virusides 2000, Mar. 13-16, 2000, Alexandria Va., page 7, abstract A10; Watanabe, M., Boyson, J. E., Lord, C. I. and Letvin, N. L. xe2x80x9cChimpanzees Immunized with Recombinant Soluble CD4 Develop Anti-self CD4 Antibody Responses with Anti-human Immunodeficiency Virus Activityxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A., 89, 5103-5107 (1992); and Perno, C. -F., Baseler, M. W., Broder, S. and Yarchoan, R., xe2x80x9cInfection of Monocytes by Human Immunodeficiency Virus Type 1 Blocked by Inhibitors of CD4-gp120 Binding, Even in the Presence of Enhancing Antibodiesxe2x80x9d, J. Exp. Med., 171, 1043-1056 (1990)).
International application published as WO 00/03998 to P. LaColla and M. Artico disclosed substituted 6-benzyl-4-oxopyrimidines useful in the treatment of HIV.
Elise A. Sudbeck, Chen Mao, Rakesh Vig, T. K. Venkatachalam, Lisa Tuel-Ahlgren, and Fatih M. Uckun disclose various dihydroalkoxybenzyloxopyrimidine derivatives shown to be effective against HIV, which were designed based on structure analysis of potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase.
Scientists have recently reported several biological discoveries that improve our understanding of how HIV enters an organism following sexual contact, which could lead to prophylactic substances that interfere with HIV""s interaction with its target cells. These discoveries revolve generally around T lymphocytes, monocytes/macrophages and dendritic cells, suggesting that CD4 cell receptors are engaged in the process of virus transmission (Parr, M. B. and Parr, E. L., xe2x80x9cLangerhans Cells and T lymphocyte Subsets in the Murine Vagina and Cervixxe2x80x9d, Biology of Reproduction, 44, 491-498 (1991); Pope, M. et al., xe2x80x9cConjugates of Dendritic Cells and Memory T Lymphocytes from Skin Facilitate Productive Infection With HIV-1xe2x80x9d, Cell, 78, 389-398 (1994); and Wira, C. R. and Rossoll, R. M., xe2x80x9cAntigen-presenting Cells in the Female Reproductive Tract: Influence of Sex Hormones on Antigen Presentation in the Vaginaxe2x80x9d, Immunology, 84, 505-508 (1995)). Geijtenbeek TBH et al., for example, recently reported that HIV tightly binds the DCxe2x80x94SIGN molecule on the surface of dendritic cells, through the gp120 HIV envelope protein. When the dendritic cells present microbial antigens to CD4+  T helper cells to stimulate an immune response, the dendritic cell inadvertently transfers the HIV to the CD4+ T cells, thereby advancing the progression of the infection.
Some have postulated, based upon these discoveries, that prophylactics can be designed that block the interaction between DCxe2x80x94SIGN and gp120. Similarly, DC4 and chemokine receptor blockers could be designed and administered to prevent the transfer of HIV from the dendritic cells to the CD4+ T cells. However, methods that rely on the specific interaction of HIV and human cells are limited, because the infection pathway has not been fully defined and may be diverse. (Miller, C. J. et al., xe2x80x9cGenital Mucosal Transmission of Simian Immunodeficiency Virus: Animal Model for Heterosexual Transmission of Human Immunodeficiency Virusxe2x80x9d, J. Virol., 63, 4277-4284 (1989); Phillips, D. M. and Bourinbaiar, A. S., xe2x80x9cMechanism of HIV Spread from Lymphocytes to Epitheliaxe2x80x9d, Virology, 186, 261-273 (1992); Phillips, D. M., Tan, X., Pearce-Pratt, R. and Zacharopoulos, V. R., xe2x80x9cAn Assay for HIV Infection of Cultured Human Cervix-derived Cellsxe2x80x9d, J. Virol. Methods, 52, 1-13 (1995); Ho, J. L. et al., xe2x80x9cNeutrophils from Human Immunodeficiency Virus (HIV)-SeronegatiVe Donors Induce HIV Replication from HIV-infected Patients Mononuclear Cells and Cell linesxe2x80x9d: An In Vitro Model of HIV Transmission Facilitated by Chlamydia Trachomatis., xe2x80x9cJ. Exp. Med., 181, 1493-1505 (1995); and Braathen, L. R. and Mork, C. in xe2x80x9cHIV infection of Skin Langerhans Cellsxe2x80x9d, In: Skin Langerhans (dendritic) cells in virus infections and AIDS (ed. Becker, Y.) 131-139 (Kluwer Academic Publishers, Boston, (1991)).
Efforts by researchers to develop an HIV vaccine have also not yet been successful. Siegel et al. reported that vaccination with inactivated SIV did not protect African Green monkeys against infection with the homologous virus notwithstanding a strong immune response to SIV. (Siegel, F., Kurth, R., and Norley, S., (1995), xe2x80x9cNeither Whole Inactivated Virus Immunogen nor Passive Immunoglobulin Transfer Protects Against SIV Infection in the African Green Monkey Natural Hostxe2x80x9d, J. AIDS, 8, 217-226).
Therefore, there remains a need for an effective topical prophylactic against the sexual transmission of HIV. It is an object of the invention, therefore, to provide topical prophylactic compositions against the sexual transmission of HIV, methods for using such compositions, and devices that deliver such compositions.
It is another object of the invention to provide compounds that have extended activity against the HIV virus.
It is another object of this invention to provide a topical composition that can be applied to the areas of skin and mucus epithelia at highest risk for exchanging HIV pathogens. Formulations of such compositions can be based upon existing topical compositions used as lubricants and contraceptives, which are often present as lotions or gels, or coated to the exterior of condoms.
It is another object of this invention to create new, long-term prophylactic methods for women based upon existing contraceptive devices, including sustained release devices to be inserted in the vagina (intra-vaginal devices such as sponges and cervical caps).
It is still another object of this invention to provide suppositories and intra-vaginal or rectal pills that can be inserted into the vagina or rectum in order to release one or more anti-HIV agents at a predetermined rate.
Yet another object of the invention is to deliver, along with the anti-HIV agent, agents against other things from which the user desires protection, such as sperm, toxins, and/or STD pathogens.
The invention provides compounds, compositions and methods for prophylactically inhibiting the spread of AIDS. The compounds of the present invention display inhibition of HIV replication, and do so for a prolonged period of time, which renders them useful in prophylactic applications, wherein the frequency or duration of use are not always predictable. The compounds are also useful in prophylactic applications because they inhibit the HIV virus upon contact at very low concentrations, before the virus has infected its host and begun replication. Non-nucleoside reverse transcriptase inhibitors (xe2x80x9cNNRTIxe2x80x9d) have proven especially invaluable in this type of application.
Thus, in one embodiment, the invention provides a method for inhibiting sexual transmission of HIV comprising topically applying to the skin or epithelial tissue of a human a composition comprising a non-nucleoside reverse transcriptase inhibitor (xe2x80x9cNNRTIxe2x80x9d) that is able to inhibit viral replication for periods exceeding 12, 24 or even 36 days, at concentrations below even 10 xcexcM.
In one embodiment the NNRTI is a dihydro-alkyloxy-benzyl-oxopyrimidine (DABO). This class of compounds is capable of inhibiting HIV multiplication targeting reverse transcriptase without bioactivation. Preferred DABOs include compounds of formula (A): 
as herein defined.
In another embodiment the invention provides a topical composition in the form of a cream, lotion, gel, or foam, comprising a dihydro-alkyloxy-benzyl-oxopyrimidine.
In still another embodiment the invention provides a composition in the form of an intra-vaginal or intra-rectal pill or suppository comprising a dihydro-alkyloxy-benzyl-oxopyrimidine.
A still further embodiment provides a device for inhibiting the sexual transmission of HIV comprising: (a) a barrier structure for insertion into the vaginal cavity, and (b) a composition comprising a dihydro-alkyloxy-benzyl-oxopyrimidine.
Still a further embodiment provides dihydro-alkyloxy-benzyl-oxopyrimidines defined by the foregoing structure.